For the purpose of extending the healthy lives of people and of improving quality of life, Ministry of Health, Labour and Welfare has drawn up “Healthy Japan 21” that is a national health promotion campaign in this century, and has taken various measures to aim at its realization. Accordingly, the development of safe and effective pharmaceutical preparations, various medicinal/therapeutic materials, health foods, and supplements is proceeding, among which synthetic polymers are expected to be utilizable since they can be easily synthesized in compliance with given functions to exhibit higher performance, as compared with natural products.
Among poly(lactic acid) synthesized from lactic acid as a raw material which is obtained from various plants such as corns and sugarcanes, high-molecular-weight poly(lactic acid) products (molecular weight of tens of thousands to hundred thousand) are utilized in large amounts as biomass plastics in the form of various molded products. These high-molecular-weight products are biodegradable and enzymatically hydrolyzed in the living body, and their degradation product, lactic acid, is further metabolized in tissues and oxidized to carbon dioxide. By utilizing this characteristic, therefore, these products are used in absorbable surgical sutures or in sustained release pharmaceutical carriers such as pellets or microcapsules for antitumor agents, hormones etc.
Conventionally, as shown in FIG. 5, such poly(lactic acid) (molecular weight of tens of thousands to hundred thousand) has been produced basically by the following 2 methods.
The first method is called a lactide method wherein lactic acid is used as a raw material to once synthesize an oligomer having a molecular weight of about 2000 with a tin compound or the like as a catalyst, and then the oligomer is subjected to heating/cyclization depolymerization to synthesize a cyclic dimer (lactide) which is then isolated and purified, followed by ring-opening polymerization of the lactide with a catalyst such as tin to synthesize poly(lactic acid).
The second method is called a direct method wherein lactic acid is similarly used as a raw material to once synthesize an oligomer having a molecular weight of about 2000 with a tin compound or the like as a catalyst, and then the oligomer is heated and dehydrated in the presence of a catalyst such as tin to synthesize a polymer having a molecular weight of several thousands which is then further subjected to thermal dehydration reactions in several stages to synthesize poly(lactic acid).
However, both these production methods usually involve reaction under a reduced pressure of 13 to 2700 Pa at a high temperature of 180 to 270° C. for one day to ten-odd days to synthesize poly(lactic acid), which is a high-cost reaction that requires a large amount of energy and time (for example, Non-Patent Document 1).
A harmful tin catalyst and various additives remain in the thus synthesized poly(lactic acid), and these foreign materials are very difficult to remove. In addition to linear products and cyclic products estimated from the reaction formula by the high-temperature and long-time reaction, various heterostructures such as branched structures and linear products having terminal groups other than hydroxy groups and carboxyl groups are further contained. Therefore, the resultant poly(lactic acid) cannot be said to be highly pure as polymer.
That is, when the poly(lactic acid) is used as a plastic material, heterostructures contained therein as impurities, similar to other condensed polymers, become severe problematic in the market to deteriorate mechanical properties and the like. In production of poly(lactic acid), heat history for a long time at high temperature is known to be a cause for increase in heterostructures (for example, Non-Patent Literature 2).
In each of these production methods, synthesis of lactic acid oligomer is the key to synthesize poly(lactic acid) since the reaction proceeds via lactic acid oligomer, and how lactic acid oligomers are efficiently synthesized exerts a significant influence on reduction in the cost of poly(lactic acid).
A lactic acid oligomer is utilized as an intermediate of poly(lactic acid), besides, it is found that the oligomer has, in addition to its high safety, an influencing action on an anaerobic glycolytic system that is an essential part of lipid metabolism and cancer cell energy metabolism, and that practical utilization of the lactic acid oligomer as an epoch-making functional food having an action of repairing and normalizing biotransformation in nutrition-associated diseases is initiated (see Non-Patent Document 3).
This lactic acid oligomer (molecular weight of 2000 or less) for functional food is introduced directly into the living body, and thus use of a toxic tin compound or the like therein should be voided as much as possible. Therefore, its synthesis is considerably troublesome in spite of its low molecular weight. At present, this oligomer is obtained by heating lactic acid for about 1 day under a reduced pressure followed by drying to give its powdered product. That is, the reaction time is so long that various heterostructures are easily produced as byproducts, thus raising problems in production and characteristics.
The lactic acid oligomers differ in physiological activities depending on whether they are in the form of linear or cyclic condensates, and such linear and cyclic condensates are estimated to be applied to products in remedy/prevention of different diseases when such lactic acid oligomers are utilized as, for example, functional food. Therefore, there is demand for development of techniques by which either linear or cyclic condensates can be distinctly produced or by which a product containing either dominantly is obtained.
The middle-molecular-weight lactic acid oligomer (molecular weight of about 5000 or more) is practically utilized as a sustained release pharmaceutical carrier. The drug release period by the middle-molecular-weight lactic acid oligomer is regulated by devices such as change in the molecular weight of the oligomer or copolymerization thereof with non-lactic-acid hydroxycarboxylic acids such as glycolic acid.
When the lactic acid oligomer is used in medical applications including sustained release pharmaceutical carriers, nonuse of harmful metal catalysts or minimum amount of byproduct impurities also become tasks to be attained from the viewpoint of safety.
If a method for producing a lactic acid oligomer with efficiency and safety by not using any harmful catalyst, solvent or additives could be found, accordingly, it would be possible to not only satisfy demand thereof as an intermediate of poly(lactic acid) but also to expect significant progress and enlargement of the industrial field thereof as a pharmaceutical and biological related material.
The present inventors have previously reported that when a metal catalyst such as tin, and microwave, are simultaneously used in the above-mentioned method of directly synthesizing poly(lactic acid), the polymerization rate increases 10-fold or more as compared with the prior art simple heating method, so that poly(lactic acid) having a molecular weight of about 20,000 is formed in only about 30 minutes (Non-Patent Document 4).
From the standpoint of strong possibility of easily giving the objective product at low cost in high yield in a short time in an environmentally sustainable manner, this prior method of directly synthesizing poly(lactic acid) is regarded as promising in industry.
However, this method is indented to synthesize high-molecular-weight poly(lactic acid) and is not related to a method for efficiently producing low-molecular-weight lactic acid oligomers wherein use of a metal catalyst such as tin is essential. It is reported that when such a catalyst is not present in this method, poly(lactic acid) is not be obtainable. Thus, there is no teaching of a method for synthesizing lactic acid oligomers safely and efficiently without using any harmful catalyst, solvent or additives.
Besides, a method of obtaining a lactic acid oligomer by polycondensation reaction of lactic acid in a household microwave oven has been proposed (Non-Patent Document 2). In this method, however, the primary structure of lactic acid oligomer cannot be regulated since the method is not capable of controlling temperature and has to be carried out under a normal pressure. Therefore, the lactic acid oligomer thus obtained by this method is poor in purity and is composed of a mixture of linear structures and cyclic structures with a large amount of structurally unclear components.    Non-Patent Document 1: “Poly(lactic acid)”, Kobunshi Kankokai, 1997, p. 14.    Non-Patent Document 2: Macromol. Rapid Commun., 2001, 22, 1063    Non-Patent Document 3: Journal of Pharmacy, 126(3), p. 28-32 (2006)    Non-Patent Document 4: Macromol. Rapid Commun., 2007, 28, 437